BACKGROUND: The collaborative quality improvement approach proposed by the Institute for Healthcare Improvement has the potential to improve coverage of evidence-based maternal and newborn health practices. The Safe Care, Saving Lives initiative supported the implementation of 20 evidence-based maternal and newborn care practices, targeting labour wards and neonatal care units in 85 public and private hospitals in Telangana and Andhra Pradesh, India. OBJECTIVE: We present a protocol for the evaluation of this programme which aims to (a) estimate the effect of the initiative on evidence-based care practices and mortality; (b) evaluate the mechanisms leading to changes in adherence to evidence-based practices, and their relationship with contextual factors; (c) explore the feasibility of scaling-up the approach. METHODS: The mixed-method evaluation is based on a plausibility design nested within a phased implementation. The 29 non-randomly selected hospitals comprising wave II of the programme were compared to the 31 remaining hospitals where the quality improvement approach started later. We assessed mortality and adherence to evidence-based practices at baseline and endline using abstraction of registers, checklists, observations and interviews in intervention and comparison hospitals. We also explored the mechanisms and drivers of change in adherence to evidence-based practices. Qualitative methods investigated the mechanisms of change in purposefully selected case study hospitals. A readiness assessment complemented the analysis of what works and why. We used a difference-in-difference approach to estimate the effects of the intervention on mortality and coverage. Thematic analysis was used for the qualitative data. DISCUSSION: This is the first quality improvement collaborative targeting neonatal health in secondary and tertiary hospitals in a middle-income country linked to a government health insurance scheme. Our process evaluation is theory driven and will refine hypotheses about how this quality improvement approach contributes to institutionalization of evidence-based practices.